title: A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.
abstract: BACKGROUND
  Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648).
  
  
  METHODS
  Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed.
  
  
  RESULTS
  28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ≥ 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks.
  
  
  CONCLUSIONS
  The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. joyce_liu@dfci.harvard.edu
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.forename: Sara M
authors.initials: SM
authors.lastname: Tolaney
authors.forename: Michael
authors.initials: M
authors.lastname: Birrer
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Mary K
authors.initials: MK
authors.lastname: Buss
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.forename: Christin
authors.initials: C
authors.lastname: Whalen
authors.forename: Karin
authors.initials: K
authors.lastname: Tyburski
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002214:Capsules; D000077216:Carcinoma, Ovarian Epithelial; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013607:Tablets; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D002214:Capsules; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D040262:Receptors, Vascular Endothelial Growth Factor; D013607:Tablets; C500926:cediranib; D007211:Indoles; C531550:olaparib
keywords: Anti-angiogenic; Breast; Cediranib; Olaparib; Ovarian; PARP-inhibitor; Phase 1